ABSTRACT AND PROJECT SUMMARY This project explores the effects of age and testosterone in determining the extent and nature of age-dependent phenotypes of peripheral -opioid receptor (MOR) expression and function. Preclinical and clinical studies continue to report effective pain management with opioids delivered to local sites. In the elderly, age-related changes can affect responses to peripheral opioid treatments. To develop rational strategies of pain management in the elderly, it is crucial to understand the effects and mechanisms of these age-related changes. Peripheral inflammation regulates MOR expression in sensory neurons in a testosterone-dependent manner, which bears important implications for older populations since testosterone levels naturally decline with aging. We hypothesize that declining testosterone levels during aging result in attenuation of peripheral MOR efficacy and impairment of MOR regulation in sensory neurons following inflammation. This hypothesis will be tested in two specific aims. In Aim 1, using our model of osteoarthritis, we will compare anti-hyperalgesic effects of DAMGO, a MOR agonist, administered at the injured site in young, middle-aged, and aged rats. We will quantify MOR expression levels in dorsal root ganglia (DRG) and determine the anti-hyperalgesic response. We predict that MOR efficacy will decrease with age since inflammation-induced upregulation of MOR expression in DRG declines with age. In Aim 2, we will investigate (1) whether testosterone supplement in middle-aged and aged rats modulates peripheral MOR expression and function, and (2) whether testosterone effects are mediated by androgen receptor (AR) in DRG. We predict that testosterone is a key modulator for peripheral MOR expression and function, and that AR functions as a transcriptional activator for MOR in DRG. Successful achievement of these aims will enhance our understanding on age-dependent changes in peripheral analgesic mechanisms and lay a foundation for the development of therapeutic strategies that can be optimally customized for the elderly as well as testosterone-compromised patient populations.